Bastiaan Geelhoed

Incidence of Atrial Fibrillation and Relationship With Cardiovascular Events, Heart Failure, and Mortality: A Community-Based Study From the Netherlands

BACKGROUND Important improvements have been made in treatment of diseases associated with atrial fibrillation (AF), such as hypertension, myocardial infarction, and heart failure. Incidence rates and risk factors may have changed with the aging of the population and changing lifestyles. Currently, the risk for AF is only partially explained, possibly because of differences between older cohorts and contemporary populations. OBJECTIVES This study investigated the incidence of AF in a contemporary cohort in the Netherlands, together with comorbidities associated with AF and associations of AF with cardiovascular outcomes. METHODS Incident AF was ascertained for hospital and study electrocardiograms in 8,265 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study in Groningen, the Netherlands. RESULTS During 9.7 ± 2.3 years of follow-up, 265 participants developed AF, with a resulting overall AF incidence of 3.3 per 1,000 person-years. Advancing age, male sex, antihypertensive drug use, higher body mass index, previous myocardial infarction, and previous stroke were associated with AF. After multivariable adjustment, AF was associated with cardiovascular events (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.06 to 4.75; p = 0.035), heart failure with either reduced or preserved ejection fraction (HR: 4.52; 95% CI: 2.02 to 10.09; p < 0.001), and all-cause mortality (HR: 3.02; 95% CI: 1.73 to 5.27; p < 0.001). CONCLUSIONS The incidence of AF in the present cohort was comparable to that shown in data of older studies. Obesity has become a major risk factor for incident AF. Although overall cardiovascular event rates were lower in the present study, the present study confirms the association of incident AF with such events.

Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Right ventricular (RV) dysfunction and pulmonary hypertension (PH) are increasingly recognized in heart failure with preserved ejection fraction (HFpEF). The prevalence and prognostic value of RV dysfunction in HFpEF have been widely but variably reported. We therefore conducted a systematic review and meta‐analysis according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses.

Genetic Risk Prediction of Atrial Fibrillation

Background: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10−3 to <1×10−8 in a prior independent genetic association study. Results: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13–1.46; P=1.5×10−4) to 1.67 (25 variants; 95% confidence interval, 1.47–1.90; P=9.3×10−15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum &Dgr;C statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39–4.58; P=2.7×10−3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20–4.40; P=0.01). Conclusions: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.

Genetic Obesity and the Risk of Atrial Fibrillation- Causal Estimates from Mendelian Randomization

Background: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. Methods: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance–weighted meta-analysis. Results: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32–0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90–1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02–1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05–1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04–1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05–1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04–1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. Conclusions: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.Background: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. Methods: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance–weighted meta-analysis. Results: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI ( FTO : 0.43 [95% confidence interval, 0.32–0.54] kg/m2 per A-allele, P <0.001; BMI gene score: 1.05 [95% confidence interval, 0.90–1.20] kg/m2 per 1-U increase, P <0.001) and incident AF ( FTO , hazard ratio, 1.07 [1.02–1.11] per A-allele, P =0.004; BMI gene score, hazard ratio, 1.11 [1.05–1.18] per 1-U increase, P <0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04–1.26) per kg/m2, P =0.005 ( FTO ) and 1.11 (1.05–1.17) per kg/m2, P <0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04–1.06] per kg/m2, P <0.001). Multivariable adjustment did not significantly change findings. Conclusions: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF. # Clinical Perspective {#article-title-71}

Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: Results of the RACE 3 trial

Aims Atrial fibrillation (AF) is a progressive disease. Targeted therapy of underlying conditions refers to interventions aiming to modify risk factors in order to prevent AF. We hypothesised that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Methods and results We randomized patients with early persistent AF and mild-to-moderate heart failure (HF) to targeted therapy of underlying conditions or conventional therapy. Both groups received causal treatment of AF and HF, and rhythm control therapy. In the intervention group, on top of that, four therapies were started: (i) mineralocorticoid receptor antagonists (MRAs), (ii) statins, (iii) angiotensin converting enzyme inhibitors and/or receptor blockers, and (iv) cardiac rehabilitation including physical activity, dietary restrictions, and counselling. The primary endpoint was sinus rhythm at 1 year during 7 days of Holter monitoring. Of 245 patients, 119 were randomized to targeted and 126 to conventional therapy. The intervention led to a contrast in MRA (101 [85%] vs. 5 [4%] patients, P < 0.001) and statin use (111 [93%] vs. 61 [48%], P < 0.001). Angiotensin converting enzyme inhibitors/angiotensin receptor blockers were not different. Cardiac rehabilitation was completed in 109 (92%) patients. Underlying conditions were more successfully treated in the intervention group. At 1 year, sinus rhythm was present in 89 (75%) patients in the intervention vs. 79 (63%) in the conventional group (odds ratio 1.765, lower limit of 95% confidence interval 1.021, P = 0.042). Conclusions RACE 3 confirms that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Trial Registration number Clinicaltrials.gov NCT00877643.

Relation of renal dysfunction with incident atrial fibrillation and cardiovascular morbidity and mortality: The PREVEND study

Aims Renal dysfunction is a risk factor for cardiovascular disease, including atrial fibrillation (AF) and mortality. However, the exact pathobiology linking different renal dysfunction measures, such as albumin excretion or glomerular filtration rate (GFR), to cardiovascular- and AF risk are unclear. In this study, we investigated the association of several renal function measures and incident AF, and whether the relation between renal measures and outcomes is modified by AF. Methods and results We examined 8265 individuals (age 49 ± 13 years, 50% women) included in the PREVEND study. We used albumin excretion (morning void and 24-h urine samples), serum creatinine, cystatin C, and Cystatin C-based, creatinine-based, and creatinine-cystatin C-based GFR as renal function measures; results: During a follow-up of 9.8 ± 2.3 years, 267 participants (3.2%) developed AF. In the multivariate-adjusted model, GFR, estimated by creatinine, cystatin C, or the combination was not associated with incident AF. However, increased albumin excretion was strongly associated with incident AF; urine albumin concentration and excretion (HRmorning void 1.10, P = 0.005 and HR24-hr collection 1.05, P = 0.033) and albumin creatinine ratio (HRmorning void 1.05, P = 0.010 and HR24-hr collection 1.06, P < 0.001). Interaction terms of incident AF and renal measures were not significant for incident cerebrovascular events, peripheral vascular events, ischemic heart disease, heart failure, and mortality. Conclusion In this community-based cohort, increased albumin excretion, and not GFR, was associated with incident AF, independent of established cardiovascular risk factors. Incidence of AF did not largely alter the association of renal dysfunction and cardiovascular outcomes.

Comparison of strain imaging techniques in CRT candidates: CMR tagging, CMR feature tracking and speckle tracking echocardiography

Parameters using myocardial strain analysis may predict response to cardiac resynchronization therapy (CRT). As the agreement between currently available strain imaging modalities is unknown, three different modalities were compared. Twenty-seven CRT-candidates, prospectively included in the MARC study, underwent cardiac magnetic resonance (CMR) imaging and echocardiographic examination. Left ventricular (LV) circumferential strain was analysed with CMR tagging (CMR-TAG), CMR feature tracking (CMR-FT), and speckle tracking echocardiography (STE). Basic strain values and parameters of dyssynchrony and discoordination obtained with CMR-FT and STE were compared to CMR-TAG. Agreement of CMR-FT and CMR-TAG was overall fair, while agreement between STE and CMR-TAG was often poor. For both comparisons, agreement on discoordination parameters was highest, followed by dyssynchrony and basic strain parameters. For discoordination parameters, agreement on systolic stretch index was highest, with fair intra-class correlation coefficients (ICC) (CMR-FT: 0.58, STE: 0.55). ICC of septal systolic rebound stretch (SRSsept) was poor (CMR-FT: 0.41, STE: 0.30). Internal stretch factor of septal and lateral wall (ISFsep–lat) showed fair ICC values (CMR-FT: 0.53, STE: 0.46), while the ICC of the total LV (ISFLV) was fair for CMR-FT (0.55) and poor for STE (ICC: 0.32). The CURE index had a fair ICC for both comparisons (CMR-FT: 0.49, STE 0.41). Although comparison of STE to CMR-TAG was limited by methodological differences, agreement between CMR-FT and CMR-TAG was overall higher compared to STE and CMR-TAG. CMR-FT is a potential clinical alternative for CMR-TAG and STE, especially in the detection of discoordination in CRT-candidates.

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10−5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10−8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

Telomere length and incident atrial fibrillation : data of the PREVEND cohort

Background The incidence of atrial fibrillation (AF) increases with age. Telomere length is considered a marker of biological ageing. We investigated the association between leukocyte telomere length and incident AF in the Dutch Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Methods We included 7775 individuals without prevalent AF, and with leukocyte telomere length measured. Mean telomere length was determined by a monochrome multiplex quantitative polymerase chain reaction-based assay. Results Mean age of our cohort was 49±13 years, and 50% were men. During a mean follow-up of 11.4±2.9 years incident AF was detected in 367 (4.7%) individuals. Telomere length was shorter in individuals developing incident AF compared to those without AF (p = 0.013). Incident AF was inversely related to the telomere length. In the quartile with the longest telomere length 68 (3.5%) individuals developed AF, in the shortest telomere length quartile 100 (5.1%) individuals (p = 0.032). Telomere length was associated with incident AF in the second shortest telomere length quartile using the longest telomere length quartile as reference (hazard ratio 1.64; 95% CI 1.02–2.66; p = 0.043). After including age or AF risk factors, the relation between telomere length and incident AF was no longer significant. We found a significant interaction of age, male sex, systolic blood pressure, BMI, heart failure, and myocardial infarction with telomere length for the association with incident AF. Conclusions We found that shorter leukocyte telomere length is not independently associated with incident AF in a community-based cohort.

Gene-gene Interaction Analyses for Atrial Fibrillation

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27–1.65, P = 4.3 × 10–8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10–7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.